Chronic rejection or bronchiolitis obliterans syndrome (BOS) has emerged as the primary obstacle to long- term survival after lung transplantation. Though the cause of BOS after lung transplantation remains unclear, identified clinical risk factors include episodes of acute rejection, lymphocytic bronchiolitis, primary graft dysfunction (PGD), gastroesophageal disease (GERD), and the development of antibodies to donor human leukocyte antigens (DSA). Preliminary data suggest that approximately 50% of lung transplant recipients develop DSA in the first year after transplantation. Experimental data suggest that DSA may have a direct pathogenic effect on the transplanted lung. In animal models, DSA can cause an airway lesion similar to chronic rejection after human lung transplantation. Studies have identified DSA as an independent risk factor for acute rejection and lymphocytic bronchiolitis, and an association between DSA and antibody-mediated rejection (AMR) exists in kidney transplantation. To test the hypothesis that treatment-induced depletion of DSA, before the onset of rejection, reduces the incidence of chronic rejection or BOS, the study will use a double blind randomized placebo controlled trial to evaluate the efficacy and safety of IVIG and anti-CD20 antibody. The study's primary endpoint consists of clearance of DSA, and the secondary endpoints include BOS-free survival, acute rejection, lymphocytic bronchiolitis, chronic rejection, infections, survival, and quality of life. As key secondary aims of the study, investigators will (1) standardize DSA testing in lung transplant recipients, and (2) use the data from the study to propose a standardized clinicopathological definition of AMR after lung transplantation based on the presence of DSA and histologic findings. The project will also establish the infrastructure for standardized collection of clinical specimens including blood, saliva, lung biopsies, and lung fluid for future studies that focus on the pathogenesis of antibody-mediated graft injury. The investigators plan to prospectively validate the DSA monitoring protocol and techniques, the definition of AMR, and the efficacy and safety of such therapy in a future large multicenter randomized controlled trial. In summary, this project addresses an important problem in the field of lung transplantation, and has the potential to change clinical practice and improve outcomes for transplant recipients. (End of Abstract) PUBLIC HEALTH RELEVANCE: In the almost 1,500 people that undergo lung transplantation each year in the U.S., rejection of the lung limits long-term survival. The proposed study uses novel techniques to monitor and treat an unusual form of rejection after lung transplantation. Findings from the study have the potential to change the routine care of lung transplant recipients and improve their quality of life and survival.